Technical Field
The present invention provides a therapeutic treatment of Usher syndrome by administering to a person in need thereof an antisense oligonucleotide (ASO) that targets the RNA transcripts of the Ush1c gene to correct defective splicing associated with the disease. More particularly, certain ASOs 8-30 mer in size of the present invention base-pair with regions in exon 3 and intron 2 of the Ush1c gene to correct for loss of gene function due to mutations in the Ush 1c gene.
Background Art
Usher syndrome is the leading genetic cause of combined blindness and deafness. Usher syndrome is an autosomal recessive disorder characterized by hearing impairment and retinitis pigmentosa (for review, Keats and Corey, 1999). Usher syndrome is the most common genetic disease that involves both hearing and vision loss. Currently, there is no cure for this debilitating disease that affects approximately 4 in every 100,000 births. There are three types of Usher syndrome that are classified by disease severity. Usher syndrome type 1 (Usher I) is the most severe form and is characterized by severe hearing loss and vestibular dysfunction at birth. Ush1 individuals begin to develop vision problems in early adolescence that progress rapidly to complete blindness. There are five genes that have been associated with Usher I: Ush1C, MYO7A, CDH23, PCDH15 and SANS.
Gene therapy is an attractive approach for Usher syndrome treatment. All types of Usher syndrome appear to be inherited recessively and caused by loss of gene function, suggesting that correction of gene expression would be therapeutic. In addition, because of the early hearing loss, Usher syndrome patients could be treated therapeutically prior to retinal degeneration. Traditional gene therapy approaches based on gene delivery is problematic for many of the Usher genes as they are very large. Therapeutic approaches using small molecules that can directly alter gene expression are attractive possibilities that have been largely undeveloped for Usher syndrome. One reason for the lack of progress in the development of therapeutics for Usher syndrome has been the lack of mouse models that accurately represent the human disease. Prior art mouse models for the disease faithfully manifest the hearing and balance disorders found in Usher syndrome but do not exhibit retinal degeneration.
A mouse model of the present invention for Usher syndrome develops both hearing and visual deficiencies characteristic of Usher syndrome. This mouse model is based on a mutation in the USH1C gene, USH1C216A, that results in the activation of a cryptic 5′ splice site that is used preferentially over the normal 5′ splice site. Splicing from the cryptic site produces a truncated mRNA and protein product. This mouse model provides an ideal tool to investigate therapeutic strategies for Usher syndrome and other diseases associated with mutations in splice sites. The present invention provides ASOs that promote correct splicing of the Ush1c216A gene and restore proper Ush1c expression in vitro and in vivo.